Letters RESEARCH LETTER

Association of Bullous Pemphigoid and Malignant Neoplasms Bullous pemphigoid (BP) is the most common autoimmunemediated subepidermal blistering skin disease and occurs mostly in elderly persons. The association of malignant neoplasms with BP has been controversial.1 This study compared the incidence of cancer in patients with BP with that of the ageand sex-matched general population. Methods | Our study cohort comprised all newly diagnosed patients with BP who were seen at the National Skin Centre in Singapore from April 1, 2004, to December 31, 2009. A diagnosis of BP was based on the presence of at least 3 of 4 criteria: (1) clinical findings consistent with BP; (2) histopathological findings of subepidermal blister; (3) a direct immunofluorescence finding of IgG and/or complement proteins along the dermo-epidermal junction; and (4) indirect immunofluorescence findings of a roof or roof-and-floor pattern or positive anti–BP180-NC16A IgG antibodies.2 Patients with BP were matched with persons in the Singapore Cancer Registry and Death Registry to identify those who had cancer and/or had died. Person-years were accrued from BP diagnosis until death, cancer diagnosis, or December 31, 2011, whichever was earliest. The expected number of cancer cases was calculated as the exposure multiplied by the incidence within each age- and sex-specific category and then summed across all categories for the period 2004-2008 in Singapore. The standardized incidence ratio was calculated as the ratio of observed to expected cancers, and 95% CIs were calculated for the standard incidence ratio based on Poisson distribution. The study was approved by the ethics committee of the National Healthcare Group, Singapore. Patient consent was waived. Results | A total of 359 patients with BP (mean age, 75.7 years; range, 27.8-100.8 years) were included (Table 1). Of these, 48 (13.4%) had a malignant neoplasm, of which 16 preceded BP diagnosis by more than 5 years (mean, 17.1 years; range, 6.826.9 years). Of the 32 recent cancers, 14 occurred within 5 years preceding BP diagnosis. The remaining 18 occurred either in the same year as a BP diagnosis (n = 4) or after BP diagnosis (n = 14). These included 6 lung cancers, 5 skin cancers (nonmelanoma), 3 colorectal cancers, 2 breast cancers, 1 pancreatic cancer, and 1 prostate cancer. The mean follow-up period from BP diagnosis was 2.5 years (range, 0.2-7.4 years); the mean time from BP diagnosis to cancer diagnosis was 0.9 years (range, –1.0 to –4.2 years). The mean time from cancer diagnosis to death was 1.3 years (range, 0-7.4 years), and 7 of the 15 deaths (46.7%) that occurred during follow-up were cancer related. jamadermatology.com

The expected number of incident cancer diagnoses after BP diagnosis was 14.48, with 14 cancers observed (within 4.2 years) after BP diagnosis, yielding an age- and sex-matched standard incidence ratio of 0.97 (95% CI, 0.53-1.62) (Table 2). There was no association with malignant neoplasms, even when cancers in the concurrent year but preceding BP diagnosis or up to 5 years preceding BP diagnosis were included. No association was observed with any particular type of malignant neoplasm. While studies initially reported an association between BP and cancer,1 subsequent studies4,5 have refuted this association, including a recent British study. 6 Although there is a possibility of increased risk of malignant neoplasm in younger patients with BP,7 we did not find this association. Discussion | Our study found no significant increase in the incidence of cancer among patients with BP compared with those in the age- and sex-matched general population. Strengths of this study included a relatively large, welldefined cohort, comprehensive patient capture at a national dermatology referral center, complete verification of cancer incidence and mortality status with the national cancer registry, and long-term follow-up. Bias toward greater surveillance for cancer was unlikely because there was no institutional practice to screen patients with BP for malignant neoplasms. Our data support the findings that BP is not associated with an increased incidence of malignant neoplasms. Thus, cancer screening may not be indicated based on a diagnosis of BP per se, but it should be individualized according to the age, history, and physical evaluation of the patient. Sophie Carrie Shan Cai, MD John Carson Allen, PhD Yen Loo Lim, MD Suat Hoon Tan, MD Mark Boon Yang Tang, MD Author Affiliations: Centre for Quantitative Medicine, Duke–National University of Singapore Graduate Medical School, Singapore, Singapore (Cai, Allen); Immunobullous Clinic, National Skin Centre, Singapore, Singapore (Lim, Tan, Tang). Accepted for Publication: November 27, 2014. Corresponding Author: Mark Boon Yang Tang, MD, National Skin Centre, 1 Mandalay Rd, Singapore 308205 ([email protected]). Published Online: February 11, 2015. doi:10.1001/jamadermatol.2014.5263. Author Contributions: Drs Cai and Allen had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Cai, Tan, Tang. Acquisition, analysis and interpretation of data: All authors. Drafting of the manuscript: Cai. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Cai, Allen.

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Table 1. Characteristics of Patients With BP in Study Cohort Patientsa Characteristic

All

With Malignancy

With Malignancy Only After BP

Without Malignancy

Total

359

48 (13.4)b

Male sex

172 (47.9)

21 (43.8)

8 (57.1)

151 (48.6)

75.7 (12.6) [27.8 to 100.8]

78.7 (11.6) [50.0 to 96.0]

77.4 (13.0) [50.0 to 92.8]

75.2 (12.7) [27.8 to 100.8]

14 (100)

255 (82.0)

Age at BP onset, mean (SD) [range], y

14 (3.9)

311 (86.6)

Ethnicity Chinese

300 (83.6)

45 (93.8)

Malay

27 (7.5)

1 (2.1)

0

Indian and other

32 (8.9)

2 (4.2)

0

Duration of follow-up, mean (SD) [range], y

2.1 (2.1) [0.0 to 8.6]

1.5 (1.7) [0.0 to 6.2]

1.9 (1.9) [0.0 to 6.2]

2.2 (2.1) [0.0 to 8.6]

−6.0 (8.67) [−26.9 to 4.2]

−6.0 (8.67) [−26.9 to 4.2]

1.3 (1.4) [0.0 to 4.2]

NA

Time from BP to cancer, mean (SD) [range], yc

26 (8.4) 30 (9.7)

Lesion distribution Localized Generalized Missing

87 (24.2)

15 (31.3)

3 (21.4)

72 (23.2)

271 (75.5)

33 (68.8)

11 (78.6)

238 (76.5)

1 (0.3)

NA

NA

1 (0.3)

Mucosal lesions Present

19 (5.3)

2 (4.2)

Absent

339 (94.4)

46 (95.8)

14 (100)

293 (94.2)

1 (0.3)

NA

NA

1 (0.3)

Missing data

0

17 (5.5)

Disease status at last follow-up Active or tapering treatment

161 (44.8)

33 (68.8)

8 (57.1)

128 (41.2)

In remission

183 (51.0)

15 (31.3)

6 (42.9)

168 (54.0)

Missing data

15 (4.2)

NA

NA

15 (4.8)

Combinationd

134 (37.3)

17 (35.4)

7 (50.0)

118 (37.9)

Corticosteroid only

180 (50.1)

27 (56.3)

7 (50.0)

153 (49.2)

24 (6.7)

2 (4.2)

1 (0.3)

NA

NA

1 (0.3)

Positive

318 (96.7)

44 (91.7)

12 (85.7)

274 (88.1)

Negative

11 (3.3)

1 (2.1)

0

10 (3.2)

Missing data

30 (8.4)

3 (6.3)

2 (14.3)

27 (8.7)

1

96 (26.7)

19 (39.6)

5 (35.7)

77 (24.8)

2

138 (38.4)

25 (52.1)

7 (50.0)

113 (36.3)

3

164 (45.7)

31 (64.6)

8 (57.1)

133 (42.8)

Systemic therapy

Other immunosuppressants only Missing data

0

21 (6.8)

Circulatory autoantibody status

Died after BP diagnosis, No. of years

Abbreviations: BP, bullous pemphigoid; NA, not applicable.

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a

Values are presented as number (percentage) unless otherwise specified.

b

Of these 48 cancers, 16 preceded the BP diagnosis by more than 5 years (mean, 17.1 years; range, 6.8-26.9 years).

c

Negative values indicate that the cancer preceded the diagnosis of BP. Positive values indicate that the cancer occurred after the diagnosis of BP.

d

Combination therapy includes both systemic corticosteroids and other immunomodulatory agents.

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Letters

Table 2. Age- and Sex-Specific Standardized Incidence Ratios of Patients With BP by Period of Malignant Neoplasm Occurrence Cohort (N = 359)

Observed Cancers (95% CI)a

SIR (95% CI)a

Expected Cancers

Malignant Neoplasm Within 5 Years Before and After BP Diagnosis All

32 (21.89-45.17)

40.02

0.80 (0.55-1.13)

Men

16 (9.15-25.98)

22.50

0.71 (0.41-1.15)

Women

16 (9.15-25.98)

17.52

0.91 (0.52-1.48)

Malignant Neoplasm in Year of Onset and After BP Diagnosis All

18 (10.67-28.45)

19.72

0.91 (0.54-1.44)

Men

10 (4.80-18.39)

11.00

0.91 (0.44-1.67)

8 (3.45-15.76)

8.72

0.92 (0.40-1.81)

14 (7.65-23.49)

14.48

0.97 (0.53-1.62)

Men

8 (3.45-15.76)

8.14

0.98 (0.42-1.94)

Women

6 (2.20-13.06)

6.34

0.95 (0.35-2.06)

Women

Malignant Neoplasm After BP Diagnosis All

Abbreviations: BP, bullous pemphigoid; SIR, standardized incidence ratio. a

Calculated using the Poisson distribution.3

Administrative, technical, or material support: Allen, Lim, Tan, Tang. Study supervision: Lim, Tang.

3. Ulm K. A simple method to calculate the confidence interval of a standardized mortality ratio. Am J Epidemiol. 1990;131(2):373-375.

Conflict of Interest Disclosures: None reported.

4. Venning VA, Wojnarowska F. The association of bullous pemphigoid and malignant disease: a case control study. Br J Dermatol. 1990;123(4):439-445.

Additional Contributions: We thank our colleagues and nurses, especially those in the Immunobullous Clinic, National Skin Centre, for their expert care in treating our patients. We also thank the team from the National Registry of Diseases Office for their invaluable help and support in providing the cancer and mortality data for this study and enabling us to conduct the data analysis at their premises. None received compensation. 1. Schroeter AL. Pemphigoid and malignancy. Clin Dermatol. 1987;5(1):60-63. 2. Cai SC, Allen JC, Lim YL, Chua SH, Tan SH, Tang MB. Mortality of bullous pemphigoid in Singapore: risk factors and causes of death in 359 patients seen at the National Skin Centre. Br J Dermatol. 2014;170(6):1319-1326.

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5. Lindelöf B, Islam N, Eklund G, Arfors L. Pemphigoid and cancer. Arch Dermatol. 1990;126(1):66-68. 6. Ong E, Goldacre R, Hoang U, Sinclair R, Goldacre M. Associations between bullous pemphigoid and primary malignant cancers: an English national record linkage study, 1999-2011. Arch Dermatol Res. 2014;306(1):75-80. 7. Ruocco E, Wolf R, Caccavale S, Brancaccio G, Ruocco V, Lo Schiavo A. Bullous pemphigoid: associations and management guidelines: facts and controversies. Clin Dermatol. 2013;31(4):400-412.

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Association of Bullous Pemphigoid and Malignant Neoplasms.

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